Sjogren's Syndrome (SS) is an autoimmune disease, characterized by widespread inflammation in the exocrine glands and other organs resulting in dryness of the lining surfaces of the body, most notably, dry mouth and dry eyes. In addition, it can involve numerous other organs such as the joints, skin and nervous system. Under this project, the GTTB- SS Clinic conducts clinical investigations and clinical trials, and collaborates with laboratory investigators in GTTB, other NIH laboratories and Institutions outside the NIH in order to understand the mechanisms underlying this disease.[unreadable] The ultimate goal of our research is to find treatments for SS that are safe, effective and target specific steps in the pathogenesis of SS. To achieve this goal, we focus our research in two broad categories. Natural history studies include observational and retrospective studies with the goal to expand our knowledge about the pathogenesis of SS, to improve our diagnostic and prognostic tools and to identify targets for new therapies. The other major area involves the evaluation of novel treatments in patients with SS. [unreadable] [unreadable] Natural history of Sjogrens Syndrome protocol[unreadable] This protocol focuses on the long-term evaluation of patients with SS and related diseases. Subjects undergo a detailed clinical and laboratory evaluation that is repeated every 1-2 years. The clinical evaluation includes a complete rheumatologic, dental and ophthalmologic examination. We have enrolled 87 new subjects. We have transitioned to an electronic clinical database that allows direct data entry by patients and investigators. We completed a pilot study demonstrating the feasibility of ultrasound guided needle biopsy of the parotid glands. This is a less invasive procedure than minor salivary gland biopsy and we plan to use it for repeat biopsies in clinical studies. [unreadable] Treatment study using an anti-LFA1 monoclonal antibody in primary Sjogrens Syndrome[unreadable] Our ultimate goal is to develop safe and effective treatments that target specific steps in the pathogenesis of SS. Our general approach is to start with early stage clinical studies (Phase I/II) to establish the safety of an intervention, and at the same time, collect data about its possible efficacy. Our goal is to understand why a particular drug targeting specific components of the immune system may or may not work. Therefore, we combine these clinical trials with thorough basic science evaluations to learn more about the pathogenesis of SS and the biologic effects of the intervention. The main goal of the Sjogrens Clinic is to perform translational research that can be best achieved in smaller studies including mechanistic studies that may be impractical in a multicenter setting. This study is using Raptiva (efalizumab, Genentech), an anti-LFA1 monoclonal antibody, which is targeting the LFA1-ICAM pathway that has several functions in Sjogrens Syndrome, including lymphocyte trafficking and antigen presentation. Raptiva is approved for psoriasis but has not been tried in SS yet. The protocol proposes to use repeat salivary gland biopsies as part of our response criteria to address the effect of the treatment on the local inflammatory process. We have enrolled six patients over the last year. Three completed the protocol, one patient has completed treatment and is in the follow up phase and two have withdrawn (one because an unexpected move overseas and one because she was not able to comply with the frequent follow ups). One additional patient has signed consent and is expected to start treatment in early October. It is too early to draw any conclusions about efficacy since the study is blinded. We plan to perform the first set of research studies looking at changes in immunological parameters in response to therapy when all patients currently being treated will have completed the study. [unreadable] [unreadable] Laboratory projects directly supporting clinical studies [unreadable] In the laboratory we have focused our efforts on various aspects of acetylcholine (Ach) and its receptors (AChR) since SS patients demonstrate multiple abnormalities of this pathway, which is crucial for the production of saliva. Sjogrens patients are thought to have autoantibodies against the muscarinic acetylcholine receptors (mAChR) which may contribute to the salivary gland dysfunction. We have evaluated several methods, such as flow cytometry withtransfected cell lines, western blot using crude cell membrane preparations from the same cells, immunomicroscopy of the cells and a peptide based ELISA. The results obtained from all these experiments confirm the mainly unpublished data from other groups that reliable and reproducible immunologic detection of these antibodies is very difficult. In addition to traditional immunologic methods we evaluated functional studies using a calcium signaling assay with cell lines transfected with various muscarinic receptors but did not get consistent results. Currently, we are evaluating a different calcium signaling assay using human salivary gland cells. Since acetylcholine receptors are also expressed on activated lymphocytes we started a project to analyze the effects of Ach on various lymphocyte subsets such as regulatory and effector T cells. Any such effect may play an important role in the local inflammatory response seen in the salivary gland of Sjogren's patients. [unreadable] We have continued to expand our DNA bank for patients with SS for genetic studies in the future both intramurally and in collaboration with other groups. Currently, we have over 200 DNA samples isolated. We have provided some of these to collaborators at Childrens Hospital in Washington, DC and University of Oklahoma to test for several polymorphisms that may be related to SS. [unreadable] We have established a collaboration with the Neurobiologics and Pain theraputics section to test Sjogrens sera for known and new autoantibodies using a novel method developed in their laboratory.[unreadable] [unreadable] Future directions[unreadable] Autonomic nervous system (ANS) dysfunction in SS[unreadable] The range of symptoms in SS suggests that there may be perturbations in the nervous and immune systems and in multiple physiological pathways through which these systems communicate and mediate each other. Autoimmunity has been viewed as the most plausible pathogenic mechanism but a significant proportion of patients do not have evidence of systemic autoimmunity, even when followed longitudinally. Compared to normal healthy individuals, SS have significantly more prevalent nervous system involvement including impaired ANS function (which regulates the homeostasis via effects on the smooth muscle, glands and cardiovascular system) unique to these patients. However, little is known, about the incidence and prevalence, underlying mechanisms and importance of the ANS in SS patients. In collaboration with the Clinical Neurocardiology section of NINDS we have developed a study to investigate ANS function in patients with SS and the association between ANS dysfunction and autoimmunity. We hypothesize that ANS dysfunction is central to the pathogenesis of SS and propose to systematically study the ANS function in our cohort of patients with primary SS compared with normative data from age and sex-matched controls. This protocol calls for a comprehensive evaluation of autonomic function, using physiological, neuropharmacologic, neurochemical, and imaging approaches, to identify consistent distinctive patterns of ANS involvement in SS and thereby improve the diagnosis and understanding of pathophysiologic mechanisms of SS. [unreadable] [unreadable] Long-term plans[unreadable] We plan to develop several early stage clinical studies (Phase I/II) targeting specific components of the underlying pathogenesis of SS. We will combine these clinical trials with thorough basic science evaluations to learn about the pathogenesis of SS and the biologic effects of the intervention.